Obesity is a huge and increasing medical problem, with inadequate therapeutic options. One approach to the treatment of obesity is long-term pharmacotherapy. While only one modestly effective drug marketed in the United States (orlistat), two drugs have recently been approved by the FDA (lorcaserin, Qsymia). The limited efficacy of single agents has lead to the idea that additional agents and combination therapy are required. Progress in FY2014 includes the following: We published a re-examination of chemical uncoupler 2,4-dinitrophenol (DNP) as a treatment for obesity in mice. DNP was an effective and widely used weight loss drug in the early 1930s. However, the physiology of DNP has not been studied in detail because toxicity, including hyperthermia and death, reduced interest in the clinical use of chemical uncouplers. To investigate DNP action, mice fed a high fat diet and housed at 30 C (to minimize facultative thermogenesis) were treated with DNP in drinking water. DNP treatment increased energy expenditure but did not change food intake. DNP-treated mice weighed 26% less than controls after 2 months of treatment due to decreased fat mass, without a change in lean mass. DNP improved glucose tolerance and reduced hepatic steatosis without observed toxicity. DNP treatment also reduced brown adipose tissue activity, demonstrating that DNP-mediated heat generation substituted for brown adipose tissue thermogenesis. At 22 C, a typical vivarium temperature that is below thermoneutrality, DNP treatment had no effect on body weight, adiposity, or glucose homeostasis. Thus, environmental temperature should be considered when assessing an anti-obesity drug in mice, particularly agents acting on energy expenditure. Furthermore, the beneficial effects of DNP suggest that chemical uncouplers deserve further investigation for the treatment of obesity and its comorbidities. We published a study that MTII, a widely used melanocortin agonist that increases metabolic rate, can also cause a transient hypometabolism and hypothermia. We propose that the hypometabolism/hypothermia is a regulated response, potentially beneficial during extreme physiologic stress. We published the effects of intermittent cold exposure (4 C for one to eight hours three times a week) on C57BL/6J mice fed a high fat diet. Despite the unchanged adiposity, the cold-treated mice showed transient improvements in glucose homeostasis. Administration of the cannabinoid receptor-1 inverse agonist AM251 caused weight loss and improvements in glucose homeostasis, but showed no further improvements when combined with cold exposure. These data suggest that intermittent cold exposure causes transient, meaningful improvements in glucose homeostasis, but without synergy when combined with AM251.